Regulation of dendritic cell function by neutrophil-derived reactive oxygen species in pulmonary aspergillosis

项目摘要/摘要 这项提案概述了卡尼纳博士的五年培训计划，以建立独立的职业生涯。 肺部和重症监护医学的研究人员。在共同导师Borna Mehrad博士的指导下 Tom Braciale，我们广泛的、长期的目标是让Cagnina博士获得新的知识和技能 成为一名独立的内科科学家所必需的，同时对 了解曲霉菌的免疫反应。曲霉是一种无处不在的霉菌，能引起 免疫受损或粘膜防御异常的宿主的临床疾病。中性粒细胞在 宿主防御这种病原体，但对这些细胞在这方面的作用知之甚少 除了它们直接的杀微生物剂作用之外。我们之前已经证明，在宿主对曲霉菌的反应过程中 肺，中性粒细胞减少导致炎性单核细胞来源的树突状细胞运输和成熟的缺陷 细胞。在这项提议的初步数据中，我们报告了中性粒细胞活性氧缺乏 产量足以诱导这种表型；在不能产生活性氧物种的宿主中， 炎性树突状细胞募集和肺损伤都依赖于肿瘤坏死因子；而中性粒细胞减少 损害对病原体的保护性免疫的发展。因此，我们试图测试 假设作为对曲霉菌的反应，依赖于活性氧的中性粒细胞信号转导到 炎性树突状细胞介导(A)对急性肺损伤的保护和(B)保护的产生 对曲霉的获得性免疫。我们将在两个具体目标下进行测试：(1)确定 中性粒细胞来源的ROS在天然免疫中调节树突状细胞功能的机制 对曲霉菌的反应和(2)确定中性粒细胞ROS在保护性适应性发展中的作用 对曲霉菌的免疫力。拟议的研究与公共卫生相关，因为它定义了一个新的 一种重要的人类病原体的寄主防御机制，应该允许未来的发展 新的治疗方法或预防策略。

PROJECT SUMMARY/ABSTRACT This proposal outlines a five-year training program for Dr. Cagnina to establish a career as an independent investigator in Pulmonary and Critical Care Medicine. Under the guidance of co-mentors Drs. Borna Mehrad and Tom Braciale, our broad, long-term objective is for Dr. Cagnina to gain new the knowledge and skills necessary to evolve into an independent physician-scientist, while making significant contributions to understanding the immune response to Aspergillus. Aspergillus species are ubiquitous molds that cause clinical disease in hosts with impaired immunity or abnormal mucosal defenses. Neutrophils play a key role in host defenses against this pathogen but little is known about the contribution of these cells in in this context beyond their direct microbicidal role. We have previously shown that, during host response to Aspergillus in the lung, neutropenia results in a defect in the traffic and maturation of inflammatory monocyte-derived dendritic cells. In the preliminary data for this proposal, we report that deficiency in neutrophil reactive oxygen species production is sufficient to induce this phenotype; that, in hosts unable to generate reactive oxygen species, both the inflammatory dendritic cell recruitment and lung injury are dependent on TNF; and that neutropenia impairs the development of protective immunity against the pathogen. We therefore seek to test the hypothesis that in response to Aspergillus, reactive oxygen species-dependent neutrophil signaling to inflammatory dendritic cells mediates (a) protection from acute lung injury and (b) generation of protective adaptive immunity against Aspergillus. We will test this under two specific aims: (1) To identify the mechanism by which neutrophil-derived ROS modulates dendritic cell function during the innate immune response to Aspergillus and (2) To define the role of neutrophil ROS in the development of protective adaptive immunity against Aspergillus. The proposed studies are relevant to public health by defining a new mechanism of host defense against an important human pathogen that should allow for future development of novel therapeutics or preventative strategies.